In recent years, the WHO’s strategic initiative to “Ending Tuberculosis” has significantly accelerated the global expansion of TB-related clinical trials, particularly in cutting-edge areas such as the development of novel anti-TB drugs, optimization of short-course therapies, and the advancement of new vaccines. However, despite the notable increase in related studies, current clinical trials continue to face several critical challenges, including the lack of reviews, fragmented research designs, and insufficient generalizability of findings. In light of these issues and the current research landscape, this study aims to systematically integrate and analyze the latest developments in global TB clinical trials. It provides a comprehensive evaluation of key trial characteristics, including countries, funding agencies, development trends, demographic representation by gender and age. By critically reviewing the progress and limitations of existing research, this study seeks to lay a solid scientific foundation for further optimizing TB prevention and treatment strategies. Furthermore, it aims to promote the transition of TB treatment to a precision medicine model, and offering both theoretical insights and practical guidance for achieving global TB control goals.

An overarching analysis of trial distributions and mechanisms reveals the complexity interplay of scientific, political, and strategic drivers shaping this field. The marked peak in trial activity between 2018 and 2023 closely aligns with the political impetus generated by the first United Nations High-Level Meeting (UNHLM) on TB in 2018. This milestone event established ambitious global prevention and treatment goals, directly catalyzing an influx of research investment worldwide [21, 22]. One striking trend is the surge in phase IV trials after 2017, reflecting an urgent global demand to assess the real-world effectiveness and safety of marketed drugs, particularly bedaquiline. This trend also signifies a broader shift in global TB strategies, away from an exclusive focus on new drugs discovery and toward the optimization of existing therapies, expanding of drug accessibility, and improvement in treatment management.

The “explosive growth” in bedaquiline-related trails (78 trials, comparable to ethambutol, a drug used for over half a century) exemplifies this transition. At a deeper level, this growth reflects a paradigmatic shift in global TB control policies. For instance, the WHO’s 2019 updated guidelines for drug-resistant TB and the End TB Strategy spurred investment in new drugs targeting resistant strains [23]. The rapid approval of bedaquiline and its swift inclusion in WHO treatment guidelines exemplify how urgent public health needs, driven by policy, can effectively steer research resources toward high-priority clinical challenges [24,25,26]. However, the persistent dominance of traditional cornerstone drugs such as isoniazid (182 trials) and rifampicin (132 trials) in the trial landscape underscores the ongoing relevance of established regimens. Their prominence reflects not only the stability and reliability of these agents but also the continuous need to enhance them, through strategies such as treatment shortening and side-effect reduction, to meet evolving clinical and public health demands.

From a geographical perspective, China and South Africa lead in the number of TB clinical trials, a reflection of their high disease burden, enhanced research capabilities, and supportive policy environments. China’s relatively high number of “Planned” trials signals continued investment and expansion in TB research, aligning with recent governmental policy shifts toward increased public health funding. In contrast, the United States and the United Kingdom are dominated characterized by a higher proportion of “Completed” trials, showcasing the maturity, efficiency, and resource integration capacity of their clinical research systems. The sustained prominence of bedaquiline in South Africa (seven trials in 2023), and its explosive growth in China (five trials) and India (two trials) in the same year, reflects the synergistic impact of WHO’s high-burden country strategy and localized innovation policies, such as China’s “Major New Drug Innovation” initiative. As core contributors to global TB research, the policy frameworks in China and South Africa play a decisive role in shaping the scale, efficiency, and innovation direction of clinical activities. China, through its “Healthy China 2030” strategy, promotes intersectoral integration, incorporates TB prevention and treatment into the national medical insurance system, and promotes the “TB-Free Community” model, efforts that collectively reduce patient financial burden and enhance diagnostic accessibility at the community level [27]. Further reinforcing this momentum, the National Health Commission, in partnership with agencies such as the National Development and Reform Commission, Ministry of Education, Ministry of Science and Technology, Ministry of Civil Affairs, Ministry of Finance, State Council Poverty Alleviation Office, and National Medical Security Administration, issued the “Action Plan to Stop TB (2019–2022)”. This top-level policy design is mirrored in China’s leading number of “Planned” trials, emphasizing forward-looking strategic planning. In parallel, AI-assisted diagnosis and tongue swab technologies have been deployed to enhance patient screening and improve trial enrollment efficiency [28,29,30]. In South Africa, TB control is integrated into the National Health Insurance (NHI) framework, with Clinical Practice Guidelines (CPGs) serving as a key mechanism for coordinating cross-sector and multi-level medical resources. The Ministry of Health-led CPGs prioritize high-burden infectious diseases, including TB, HIV/AIDS, and malaria), by promoting standardized, evidence-based treatment pathways. Meanwhile, other developers such as professional societies and clinical collaboration groups predominantly focus on non-communicable diseases, highlighting the strategic prioritization of TB within the national health agenda. These efforts aim to establish a unified and efficient coordination mechanism for the NHI implementation and universal healthcare system [31]. Moving forward, the “policy-technology-guarantee” triad model exemplified by China and South Africa should be transplanted to other high-burden regions. Such translation of best practices could help narrow global disparities in TB research efficiency, enabling more precise alignment between resource allocation and public health priorities.

The distribution of funding entities in TB clinical trials further reveals underlying financial flows and their driving factors. Academic institutions remain the predominant funders, underscoring the critical role of basic research in the development of TB therapeutics. However, the relatively limited involvement of major pharmaceutical companies suggests a focus on more lucrative therapeutic areas, suggesting the need to strengthen public–private partnerships to attract more industrial investment in TB research. The active participation of non-profit entities and collaborative organizations helps to bridge funding gaps, highlighting the importance of public-interest research in addressing global public health challenges. Notably, major global health actors such as the Global Fund and the Bill & Melinda Gates Foundation play a critical support in supporting innovation in TB drug, offering financial and strategic backing for high-impact initiatives [32, 33].

The demographic distribution of participants in clinical trials for novel anti-TB drugs serves as a critical lens through which to examine the evolution of global public health policies, shifting priorities in drug-resistant TB control, and advances in research ethics. Bedaquiline, delamanid, and pretomanid, as core drugs in drug-resistant TB treatment, exhibit imbalances in both gender and age representation across clinical trials, revealing structural tensions between research strategies and real-world population needs. Trial design data indicate a strong bias toward “all-population applicable” (Both category) with bedaquiline reporting 68 trials compared to only three gender-specific trials, delamanid 40 vs. 1; pretomanid 34 vs. 3. Gender-specific trials were largely absent before 2019 and only began to emerge sporadically thereafter. A turning point came with the 2018 WHO guideline update on multidrug-resistant TB, which explicitly called for the inclusion of special populations, such as individuals co-infected with HIV, children, and women of childbearing age [34]. This policy directive catalyzed a modest but important increase in gender-specific trials after 2021, including bedaquiline’s first female-specific trial. The influence of policy levers is further validated in the age distribution of trial participants. Before 2013, clinical trials were nearly absent, only 1 trial across all three drugs included children. This landscape began to shift following the launch of United Nations Children’s Fund (UNICEF) 2013 “Roadmap for Childhood TB: Toward Zero Deaths”, and particularly after the implementation of the 2018 “Roadmap towards ending TB in children and adolescents”. This initiative, coupled with Global Fund–targeted financing and administrative measures such as accelerated regulatory pathways for pediatric formulations, have systematically reduced research barriers and promoted a steady rise in pediatric trials [35]. Interestingly, trial coverage of the elderly population (≥ 65 years) shows drug-specific patterns. Bedaquiline showed elderly representation in 29% of its trials (34 out of 117), significantly higher than pretomanid’s 18% (18 out of 59). This discrepancy is closely related to bedaquiline’s known cardiotoxicity, particularly its QT interval, prolonging effect, which poses heightened risks is particularly prominent in elderly populations with cardiovascular diseases [36,37,38]. As a result, regulatory authorities have increasingly required pharmaceutical companies to supplement safety data in this demographic, reflecting a “risk-driven” allocation logic in clinical research planning.

In summary, the gender and age distribution of participants in trials of novel anti-TB drugs not only reflect clinical practices but also serve as barometers of policy effectiveness, research direction, and promotion barriers. Although WHO guidelines have significantly accelerated the adoption of new drugs, the legacy of gender underrepresentation persists, and pediatric drug data remain insufficient. At the same time, the rising inclusion of elderly patients underscores growing awareness of the complex safety considerations in this vulnerable group. The abnormal peaks in the data provide important signals for tracking emerging research priorities and evaluating the effects of global health interventions. In the future, efforts should focus on building an evidence-based drug for inclusive drug use that comprehensively addresses women, children, and elderly populations, and on advancing precision medicine approaches for complex elderly cases. Such strategies are essential to ensuring the equitable, safe, and efficient clinical application of next-generation anti-TB drugs.

Although this study has conducted an in-depth analysis of the field of tuberculosis clinical trials, there are still certain limitations. Firstly, the data mainly rely on a single database (INFORMA), which may lead to the omission of trials on unregistered or regional platforms, resulting in an underestimation of the research activity in low- and and middle-income countries. Secondly, the included trials have high heterogeneity (e.g., phase I and phase IV trials co-exist), and the statistical methods are limited to descriptive analysis, failing to deeply quantify the impact of confounding factors such as policy intensity and funding scale on the trial results. Moreover, the study has not fully explored the translation efficiency between clinical trial results and actual public health practices, especially the accessibility and affordability in resource-limited areas. To address these limitations, future research should integrate data from multiple databases and regional platforms, use stratified analysis and advanced statistical methods to quantify the impact of confounding factors, and strengthen the evaluation of the translation efficiency of clinical trial results, particularly for practical applications in resource-limited areas.